Inhibition of human recombinant LTA4 hydrolase expressed in SF9 cells using LTA4 as substrate assessed as LTB4 production incubated for 10 mins prior to substrate addition measured after 10 to 30 mins by enzyme immunoassay

Previously, benzthiazole containing LTA(4)H inhibitors were discovered that were potent (1-3), but were associated with the potential for a hERG liability. Utilizing medicinal chemistry first principles (e.g., introducing rigidity, lowering cLogD) a new benzthiazole series was designed, congeners of 1-3, which led to compounds 7a, 7c, 12a-d which exhibited LTA(4)H IC(50)=3-6 nM and hERG Dofetilide Binding IC(50)=8.9-> >10 muM. ..more

Abstract: Previously, benzthiazole containing LTA(4)H inhibitors were discovered that were potent (1-3), but were associated with the potential for a hERG liability. Utilizing medicinal chemistry first principles (e.g., introducing rigidity, lowering cLogD) a new benzthiazole series was designed, congeners of 1-3, which led to compounds 7a, 7c, 12a-d which exhibited LTA(4)H IC(50)=3-6 nM and hERG Dofetilide Binding IC(50)=8.9-> >10 muM. (PMID: 23127888)